Erythropoietin, the principle regulator of erythropoiesis, is upregulated in response to hypoxic stress resulting in increased red blood cell production to increase oxygen delivery. However, erythropoietin receptor is also expressed in other tissue including high level in embryonic brain of mice. Selective rescue of erythropoietin receptor to restore expression in erythroid tissue but not in brain results in viable mice with decreased neurogenesis and increased susceptibility to insult, suggesting neural activity of endogenous erythropoietin. Unexpectedly, mice expressing erythropoietin receptor only in erythroid cells also exhibit glucose intolerance and increased fat mass accumulation. No differences in food intake were observed, but these mice exhibited increased energy efficiency and decreased energy expenditure. Erythropoietin treatment in wild type mice stimulated erythropoiesis and also decreased fat mass accumulation and blood glucose. Erythropoietin treatment in mice with erythropoietin receptor restricted to erythroid tissue exhibited increased hematocrit, but the change in fat mass accumulation compared with saline treatment observed in wild type mice was not evident. High level of erythropoietin receptor expression was observed in white adipose tissue and in the proopiomelanocortin neurons of the hypothalamus. While erythropoietin treatment in wild type mice induces the expression of the polypeptide hormone precursor gene, proopiomelanocortin, mice lacking erythropoietin receptor show reduced levels of proopiomelanocortin in the hypothalamus. Furthermore, in an in vitro model of adipogenesis using primary mouse embryonic fibroblasts, erythropoietin inhibited adipogenesis, activated signal transduction pathways and increased PPARgamma phosphorylation, a transcription factor required for adipogenesis. These data suggest that in addition to erythroid tissue, endogenous erythropoietin signaling is functional in select non-hematopoietic tissue such as brain and white adipose tissue, and contributes to energy homeostasis.

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